Biologics in the treatment of skin and rheumatologic diseases

Introduction.

The past 25 years has witnessed an escalation in treatments for inflammatory and autoimmune diseases due to incorporation of targeted biologic therapies into clinical care. Currently, over 30 FDA-approved “biologics” are in use for nearly as many different immune diseases, targeting a broad array of specific inflammatory mediators (Figure 1), with multiple additional biologics currently in development for an expanded range of clinical indications. While most clinicians think of biologics as monoclonal antibody-based therapeutics, the term “biologic” refers to any pharmaceutical drug manufactured in or extracted from biological sources. In this review we restrict the focus to monoclonal antibody therapeutics (referred to here as biologics) and recombinant protein mediators used to treat inflammatory conditions.

Figure 1.

Cytokine targets and approved biologics used to treat inflammatory diseases.

Structure and nomenclature of biologics.

Antibody structure comprises two distinct regions: the Fab region, that binds the target antigen, and the Fc domain, which interacts with cell surface Fc receptors and the complement system. The Fc domain imparts serum half-life through interaction with neonatal receptor FcRn¹. The four IgG isotypes differentially engage activating (FcγRI, FcγRIIa and FcγRIIIa) or inhibitory (FcγRIIb and FcγRIIIb) receptors with different affinities and bind C1q to recruit immune effector function and complement-dependent cytotoxicity¹. Therefore, the isotype of the biologic has therapeutic implications. Where effector function is desirable, IgG1 is preferred, whereas if not, IgG2 or IgG4 isotypes are selected. IgG3 is not used for antibody-based therapeutics because of instability.

Biologic nomenclature follows a scheme outlined by the World Health Organization’s International Nonproprietary Names. Biologics based on monoclonal antibodies have the stem ”-mab” as long as at least one variable domain is included. Fusion proteins consisting of a receptor fused with an IgG have the stem “-cept”. Until 2017, most biologics included a substem for the source of the monoclonal antibody, with “-o-“ referring to mouse; “-u-“ human; “-xi-“ chimeric and “-zu-“ humanized antibodies.

Immune targeting by biologics.

At least 9 different cytokines or cytokine families are currently targeted by an existing biologic including TNF, IL-1, IL-4/IL-13, IL-5, IL-6, IL-12, IL-17, IL-22 and IFN-γ. Cell surface molecules targeted by biologics include CD20, CD80, CD25, CD52 and integrins. Other targets include IgE and BAFF. Targets and FDA-approved clinical indications are shown in Figure 1, and the approved biologics for each disease are shown in Figure 2. Psoriasis has the greatest number of approved biologics, followed closely by rheumatoid arthritis (RA) and psoriatic arthritis (Figure 2), but the vast majority of inflammatory diseases have only a single approved biologic. Numerous biologics are in clinical development and will greatly expand both the number of agents for each disease and to wider clinical indications. For example, the bispecific biologic bimekizumab, which targets both IL-17A and IL-17F, shows promising results in psoriasis and PsA. Other bispecific and polyspecific monoclonal antibodies are under development and have several advantages over monoclonal antibodies as they can simultaneously block two or more unique or overlapping inflammatory pathways, and/or potentially increase binding specificity by interacting with two or more different cell surface antigens². Leprikizumab, an anti-IL-13 biologic, is currently in clinical trials for atopic dermatitis. Biologics targeting the IL-36 receptor have shown promise in generalized pustular psoriasis. Lastly, anifrolumab, a monoclonal antibody that blocks the type I IFN receptor, demonstrated efficacy for SLE, primarily in skin and joint indices³.

Figure 2. Biologics currently in use for treatment of various inflammatory diseases.

Psoriasis has the greatest number of approved biologics (12 in total) but Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) have the greatest number of classes of biologics approved (5 for each).

Paradoxical reactions and other side effects of biologics.

The specific targeting by biologics may occasionally allow immune responses to circumvent the blockade, leading to worsening disease activity. These types of reactions, termed “paradoxical adverse reactions”, often manifest as a shift in clinical presentation or presentation of a “new” inflammatory disease. Paradoxical adverse reactions are more common in women⁴ often arising in the setting of treatment for chronic inflammatory diseases such as psoriasis, RA, ankylosing spondylitis and Crohn’s disease⁴. They frequently manifest in the skin and less commonly as new onset inflammatory bowel disease⁵ or arthritis⁶. A common presentation is palmoplantar pustular psoriasis⁴, but other reactions such as new onset psoriasis, lichen planus-like eruption, worsening eczema or alopecia areata have been reported.

Monitoring of biological treatments and treatment failures.

The great majority of biologics used to treat inflammatory conditions are given as chronic suppressive therapy, as treatment interruptions or “vacations” increases risk of disease recurrence and treatment failure⁷. Frequent reason for discontinuation of a biologic across diseases is loss of efficacy, followed by physician preference, safety, patient preference, and lack of access to treatment⁸. While primary treatment failures occur, many initially responsive patients also end up failing treatment after a period of a few months to a few years (secondary treatment failure), and the risk of failure over time is greater, and more rapid, the higher the number of prior biologics a patient has used⁹. Three broad categories of biologic failure are recognized and can help to identify non-responders who may benefit from dose escalation versus transition to an alternative therapeutic class. In mechanistic failure, biologic level is optimal but clinical response is inadequate, indicating a need to target an alternative disease mechanism. Such patients are unlikely to benefit from transition to another drug of the same class. In immune-mediated pharmacokinetic failure, biologic level is subtherapeutic in the presence of high titers of neutralizing anti-drug antibodies (ADAs). In non-immune-mediated pharmacokinetic failure, the biologic level is subtherapeutic in the absence of ADAs, often due to rapid clearance in the setting of high inflammatory burden¹⁰. Several factors have been implicated in these failures such as body mass index (BMI), where increased BMI is associated with reduced response to multiple biologics. In addition, there are prominent sex differences, with men being more likely to achieve better initial response than women and less likely to discontinue therapy across a range of different immune disease.

Conclusion

Despite enormous progress and availability of numerous biologics, treatment indications and insurance coverage remain highly disease-centric, and this is a major reason for the slow adaptation of these agents for broader use. Future progress towards an inflammation-centric and personalized approach is likely to revolutionize our abilities to treat patients with these frequently devastating immunological diseases.